The United States has been led to an inflection point at which its biomedical research-driven plan should be improved to effectively address the health consequences of the opioid epidemic.
Two major changes in the focus for National Institutes of Health (NIH)–funded research are needed in order to fulfill this matter, which will hopefully develop practical information and critically needed new treatments for opioid addiction.
First, NIH-funded research currently focuses on the later stages of drug addiction that are associated with drug craving and relapse. Nonetheless, prevention strategies that target the early stage of drug addiction should be developed since the opioid epidemic has a large iatrogenic component.
Secondly, to change the focus, an in-depth understanding of opioid neurobiology is required. Opiate-induced changes in synaptic signaling should be characterized, rather than examining opiate-induced changes only at the neural circuit level or with brain imaging to identify involved brain regions.
An Iatrogenic Basis for the US Opioid Problem
In the United States, a change in the pattern of drug abuse became evident more than 10 years ago: major driver of opioid abuse had become prescription opioids. Compared to the street value, high-potency opioids (hydrocodone, oxycodone) were prescribed by physicians. Moreover, patients made an increased number of physician visits to obtain opioids (32 million per year). The associated increase in the number of opioid prescriptions has amplified the rates of opioid misuse and fatal opioid overdose, even more than any other illicit drugs combined.
Three Stages of Opioid Addiction
Stage One – binge/intoxication: involves opiate-induced reward sensations in the brain.
Stage Two – withdrawal/negative affect: is characterized by an elevation in the threshold for experiencing the reward sensation after drug use (i.e., increased exposure to the drug is required) and a withdrawal state occurs when the drug cannot be obtained.
Stage Three – preoccupation-relapse: is characterized by chronic relapse in drug use, often triggered by environmental and emotional signals.
Neurochemical changes alter brain circuits when the severe use of opioid is induced. This reduces the reward sensation experienced during the initial stage and increases the stress and compulsivity associated with chronic drug addiction.
A Better Direction for Research
Understanding and treating the later stage of drug addiction, with the goal of evolving therapies to diminish drug craving and relapse, is the current focus of the research. Less emphasis is now placed on developing a preventive approach, which targets the first stage in the drug addiction cycle as a result of this approach. Preventing a person who takes opioid analgesics for a short duration from becoming a long-term user, is the method to achieve prevention. This approach is different from the notion of preventing access to opioids. Nonetheless, the central importance of opioid analgesics in medical practice and the absence of reliable substitute analgesic medications is not considered by this notion. It also neglects the concept that treatments are more likely to fail when drug addiction has reached an advanced stage when many more brain circuits are involved.
Identifying the neural circuits altered by opioid addiction is the focus of current research programs. However, there is a possibility that a general opiate-induced maladaptation develops in various brain circuits. When they are examined solely at the neural circuit level, maladaptive changes could be better understood when opiate-induced changes in molecular signaling are portrayed. In addition, usurping mechanisms that the brain uses for learning and for storing memories is the pathway that addicted state is reached. With a better understanding of the involved pathways in the first stage, new therapeutic methods for the later stages could also be rationally developed.
Prevention Strategies Have Delivered Many Benefits
While most US health care spending (and most research spending) targets treatment of diseases, preventive measures have significantly improved public health, such as immunization programs for infectious diseases, colonoscopy or Pap smears for cancer prevention, folic acid supplementation to prevent neural tube defects, and the use of car seats and seat belts in automobiles.
Even though there is an ongoing debate about where health care money is best spent, almost all clinicians and public health experts come to an agreement that it is superlative if a disease can be prevented from developing, and a disease is more easily treated at early stages before it is fully developed.
NIH-funded research intends to focus on community prevention programs by addressing substance misuse and other youth problems. These cost-effective programs are important to the public.
Would a Prevention Strategy Be Useful?
The recent study showed the benefits of a therapy that targets early stages of opioid addiction which are suggested by data that examined the probability of long-term opioid use (>1 year) after opioid-naive patients received an opioid prescription. If the initial period of opioid use was at least 1 day, a person had a 6% chance of becoming a chronic opioid user (one who continues using opioids 1 year later), and the probability increased to 13.5% if opioids were used for at least 8 days, which was the period covered by 30% of opioid prescriptions. The number of individuals at risk for chronic opioid abuse is substantial because US physicians wrote 66.5 opioid prescriptions for every 100 persons in 2016. Hence, there could be a substantial decrease of the opioid epidemic in the United States, when a method is executed, which could prevent dependence from developing in opioid-naive individuals.
Susceptibility of each person to opioid addiction varies. Although there is a 50% genetic predisposition in individual’s addiction vulnerability, through all classes of drugs of abuse, an individual with a relatively low genetic risk profile will become addicted after exposure to a sufficient dose of opioids for a sufficient period of time. This factor is very important because very potent opioids are prescribed.
Could a Prevention Strategy Be Developed?
Implementation of methods that could prevent addiction from occurring is highly favored by the iatrogenic origin of most of the opioid problems. Clinicians know when opioid-naive patients are initially exposed to opioids. Unlike illicit drugs, there is an evidence that makes it possible to develop techniques to decrease the probability that opioid-naive individuals would become addicted after a short-term opioid treatment. For example, it was recently
demonstrated that a commonly used 5-HT3A receptor (5HT3AR) antagonist (ondansetron) had an unexpectedly profound effect on early-stage opioid responses; it substantially reduced the symptoms of experimentally induced opioid withdrawal in opioid-naive mice and humans. The major gaps in understanding the early-stage opioid response are illustrated by the fact that the ondansetron effect was unexpected, and its mechanism of action remains unexplained.
Early results with a commonly used and safe medication may be possible to reduce the probability that an individual will become addicted to opioids following initial exposure. Also, new forms of opioid medications that have a reduced tendency to produce dependence, but retain its analgesic effects, can potentially be produced. Early outcomes also attest that an improved research agenda that focuses resources on a deeper understanding of opioid neurobiology, as well as prevention of opioid exposure among
high-risk individuals will make it more likely that the clinical and public health response to the opioid epidemic could be effective.
This research will undoubtedly be of great influence as it employs strategies and measures to prevent opioid addiction and increase the rate of survival.